US7029681B2 - Multiple and multivalent DNA vaccines in ovo - Google Patents

Multiple and multivalent DNA vaccines in ovo Download PDF

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US7029681B2
US7029681B2 US10/377,718 US37771803A US7029681B2 US 7029681 B2 US7029681 B2 US 7029681B2 US 37771803 A US37771803 A US 37771803A US 7029681 B2 US7029681 B2 US 7029681B2
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virus
avian
fowl
dna
egg
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US20030175291A1 (en
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Tsun Yung Kuo
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Schweitzer Chemical Corp
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Schweitzer Chemical Corp
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Priority to US10/377,718 priority Critical patent/US7029681B2/en
Priority to PCT/US2003/006811 priority patent/WO2003075843A2/en
Priority to IL16385903A priority patent/IL163859A0/xx
Priority to EP03744203.5A priority patent/EP1490105B1/en
Priority to JP2003574119A priority patent/JP4999258B2/ja
Priority to MXPA04008692A priority patent/MXPA04008692A/es
Priority to CN038080001A priority patent/CN1646157B/zh
Priority to CA2478081A priority patent/CA2478081C/en
Priority to CN200910212389A priority patent/CN101703770A/zh
Priority to BRPI0308365A priority patent/BRPI0308365B1/pt
Priority to AU2003216531A priority patent/AU2003216531B2/en
Priority to US10/429,735 priority patent/US7037506B2/en
Publication of US20030175291A1 publication Critical patent/US20030175291A1/en
Priority to IL163859A priority patent/IL163859A/en
Publication of US7029681B2 publication Critical patent/US7029681B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/53—DNA (RNA) vaccination
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/70—Multivalent vaccine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16311—Mardivirus, e.g. Gallid herpesvirus 2, Marek-like viruses, turkey HV
    • C12N2710/16322—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2720/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsRNA viruses
    • C12N2720/00011—Details
    • C12N2720/10011—Birnaviridae
    • C12N2720/10022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/18011—Paramyxoviridae
    • C12N2760/18111—Avulavirus, e.g. Newcastle disease virus
    • C12N2760/18122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20022—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Definitions

  • the present invention relates to either a muliple DNA vaccine or a multivalent DNA vaccine for use in aquiring embroyonic immunity in fowl eggs and methods for preparing and using the same.
  • the multiple DNA vaccine contains two or more DNA constructs, each containing a DNA molecule encoding an avian viral protein or a fragment thereof capable of inducing a protective immune response against an avian viral disease in fowl.
  • the multivalent DNA vaccine contains a DNA construct which contains two or more DNA molecules. Each of the DNA molecules represents an avian viral gene or a fragment thereof.
  • the multivalent DNA vaccine is capable of expressing two or more viral antigens and inducing protective immune responses against two or more of the avian viral diseases in fowl. Both the multiple DNA vaccine and the multivalent DNA vaccine are preferred to be injected into the amniotic fluid of the fowl egg after being fertilized for about 18 days.
  • MDV Marek's disease virus
  • IBDV infectious bursal disease virus
  • NDV Newcastle disease virus
  • IBV infectious bronchitis virus
  • ILTV infectious laryngotracheitis virus
  • AEV avian encephalomyelitis
  • CAV chick anemia virus
  • FMV Fowlpox virus
  • AIV avian influenza virus
  • AIV reovirus
  • ALV reticuloendotheliosis virus
  • HEV hemorrhagic enteritis virus
  • Marek's Disease is a malignant, lymphoproliferative disorder disease that occurs naturally in chickens. The disease is caused by a herpesvirus: Marek's Disease Virus (MDV). MD is ubiquitous, occurring in poultry-producing countries throughout the world. Chickens raised under intensive production systems will inevitably suffer losses from MD. The symptoms of MD appear widely in the nerves, genital organs, internal organs, eyes and skin of the infected birds, causing motor trouble (due to paralysis when the nerves have been affected), functional trouble of the internal organs (due to tumors), and chronic undernourishment (if the internal organs are attacked by the virus). MD affects chickens from about 6 weeks of age, occurring most frequently between ages of 12 and 24 weeks.
  • MDV Marek's Disease Virus
  • control of the disease is based primarily on management methods such as insolating growing chickens from sources of infection, the use of genetically resistant stock, and vaccination.
  • management procedures are normally not cost-effective and the progress has been disappointing with respect to the selection of poultry stock with increased genetically controlled resistance.
  • control of MD is almost entirely based on vaccination.
  • IBDV Infectious bursal disease virus
  • IBD infectious bursal disease
  • IBDV is a member of the Birnaviridae family and its genome consists of two segments of double-stranded RNA (See Dobos et al (1979), J. Virol., 32:593–605).
  • the smaller segment B (about 2800 bp) encodes VP 1, the dsRNA polymerase.
  • the larger genomic segment A (about 3000 bp) encodes a 110 kDa precursor polypeptide in a single open reading frame (ORF) that is processed into mature VP2, VP3 and VP4 (See Azad et al (1985), Virology, 143:35–44). From a small ORF partly overlapping with the polypeptide ORF, segment A can also encode VP5, a 17-kDa protein of unknown function (See Kib
  • VP2 and VP3 are the major structural proteins of the virion, VP2 is the major host-protective immunogen and causes induction of neutralizing antibodies (See Becht et al. (1988), J. Gen. Virol., 69:631–640; Fahey et al. (1989), J. Gen. Virol., 70:1473–1481).
  • VP3 is considered to be a group-specific antigen because it is recognized by monoclonal antibodies (Mabs) directed against VP3 from strains of both serotype 1 and 2 (See Becht et al (1988), J. Gen. Virol., 69:631–640). (See Jagadish et al. (1988), J. Virol., 62:1084–1087).
  • Efforts to develop a recombinant vaccine for IBDV have also been made, and the genome of IBDV has been cloned (See Azad et al (1985) “Virology”, 143:35–44).
  • the VP2 gene of IBDV has been cloned and expressed in yeast (See Macreadie et al. (1990), Vaccine, 8:549–552), as well as in recombinant fowlpox virus (See Bayliss et al (1991), Arch. Virol., 120:193–205).
  • antisera afforded passive protection in chickens against IBDV infection.
  • the fowlpox virus-vectored VP2 antigen afforded protection against mortality, but not against damage to the bursa of Fabricius.
  • Newcastle disease virus is an enveloped virus containing a linear, single-strand, nonsegmented, negative sense RNA genome.
  • virus families containing enveloped single-stranded RNA of the negative-sense genome are classified into groups having non-segmented genomes (e.g., Paramyxoviridae and Rhabdoviridae) or those having segmented genomes (e.g., Orthomyxoviridae, Bunyaviridae and Arenaviridae).
  • NDV together with parainfluenza virus, Sendai virus, simian virus 5, and mumps virus, belongs to the Paramyxoviridae family.
  • the structural elements of the NDV include the virus envelope which is a lipid bilayer derived from the cell plasma membrane.
  • the glycoprotein, hemagglutinin-neuraminidase (HN) protrude from the envelope allowing the virus to contain both hemagglutinin and neuraminidase activities.
  • the fusion glycoprotein (F) which also interacts with the viral membrane, is first produced as an inactive precursor, then cleaved post-translationally to produce two disulfide linked polypeptides.
  • the active F protein is involved in penetration of NDV into host cells by facilitating fusion of the viral envelope with the host cell plasma membrane.
  • the matrix protein (M) is involved with viral assembly, and interacts with both the viral membrane as well as the nucleocapsid proteins.
  • the main protein subunit of the NDV nucleocapsid is the nucleocapsid protein (NP) which confers helical symmetry on the capsid.
  • NP nucleocapsid protein
  • P phosphoprotein
  • L L protein
  • the phosphoprotein (P) which is subject to phosphorylation, is thought to play a regulatory role in transcription, and may also be involved in methylation, phosphorylation and polyadenylation.
  • the L gene which encodes an RNA-dependent RNA polymerase, is required for viral RNA synthesis together with the P protein.
  • the L protein which takes up nearly half of the coding capacity of the viral genome is the largest of the viral proteins, and plays an important role in both transcription and replication.
  • RNA viruses including NDV
  • NDV negative-strand RNA virus
  • mRNA positive-strand
  • the L, P and NP proteins must enter the cell along with the genome on infection.
  • vRNAs NDV negative strand genomes
  • cRNAs antigenomes
  • the cytoplasm is the site of NDV viral RNA replication, just as it is the site for transcription. Assembly of the viral components appears to take place at the host cell plasma membrane and mature virus is released by budding.
  • EMS ethyl methane sulfonate
  • EMS is a mutagen so that the vaccine prepared by the use of EMS is suspected to act as a mutagen as well, which is undesirable for regular administration of the vaccine.
  • the NDV vaccine cannot be applied for in ovo vaccination as almost all of the embryos will die upon injection of the eggs with the unmodified virus.
  • IBV Infectious bronchitis virus
  • IB infectious bronchitis
  • the virus has a single-stranded RNA genome, approximately 20 kb in length, of positive polarity, and is usually about 80–100 nm in size, being round with projecting 20 nm spikes.
  • IBV is the causative agent of an acute, highly contagious disease in chickens of all ages, affecting the respiratory, reproductive and renal systems.
  • IBV contains three structural proteins: the spike (S) glycoprotein, the membrane glycoprotein, and the nucleocapsid protein.
  • the spike glycoprotein is so called because it is present in the teardrop-shaped surface projections or spikes protruding from the lipid membrane of the virus.
  • the spike protein is believed likely to be responsible for immunogenicity of the virus, partly by analogy with the spike proteins of other corona-viruses and partly by in vitro neutralisation experiments (See, e.g., D. Cavanagh et al. (1984), Avian Pathology, 13, 573–583).
  • the polypeptide components of the glycopolypeptides S1 and S2 have been estimated after enzymatic removal of oligosaccharides to have a combined molecular weight of approximately 125,000 daltons. It appears that the spike protein is attached to the viral membrane by the S2 polypeptide.
  • IBV has been wide-spread in countries where an intensive poultry industry has been developed. Young chickens up to 4 weeks of age are most susceptible to IBV, infection leading to high rates of morbidity and to mortality resulting from secondary bacterial infection. Infection also results in a drop in egg production, or failure to lay at full potential, together with an increase in the number of down-graded eggs with thin, misshapen, rough and soft-shells produced, which can have a serious economic effect.
  • Administering live vaccines to a developing chick in the egg (in-ovo) has proven to be a fast (40,000 eggs per hour), effective (100% of the eggs receive the vaccine), and labor saving ($100,000 per year per hatchery) method to vaccinate baby chicks against certain diseases before they hatch.
  • the first in-ovo vaccination machine for use on chicken hatching eggs was developed by Embrex, Inc., of Raleigh, N.C. in the late 1980s. (See U.S. Pat. Nos. 5,056,464 and 5,699,751).
  • This in-ovo machine is currently used in about 80% of the U.S. broiler hatcheries, primarily for administering MD vaccines.
  • the popularity of this machine which has proven to be safe and effective in vaccination of chicks against MD, is also being used increasingly to administer IBD vaccines and ND vaccines.
  • DNA vaccines a DNA-mediated immunization
  • the multiple DNA vaccine of the present invention contains a combination of two or more DNA construct, each containing a single DNA molecule which is a viral gene or a fragment thereof.
  • the multivalent DNA vaccine of the present invention contains two or more viral genes or fragments thereof linking together in one DNA construct.
  • the viral genes or fragments used in preparation of either the multiple DNA vaccine or the multivalent DNA vaccine are those that encode viral peptides which are antigenic to and can induce both the humoral and the cellular immune system in a host.
  • the DNA vaccines are preferably applied to the egg by needles.
  • the injection of the DNA vaccines in ovo leads to surprisingly strong immune responses which include not only antibody induction and T-cell activation with cytokine secretion, but also the production of cytotoxic T lymphocytes (CTL).
  • CTL cytotoxic T lymphocytes
  • the present invention provides a multiple DNA vaccine for in ovo injection.
  • the multiple DNA vaccine contains two or more DNA constructs, each DNA construct expressing an antigenic protein of an avian virus causing avian viral disease in fowl.
  • the antigenic protein of the avian virus is capable of inducing a protective immune response against an avian viral disease.
  • the multiple DNA vaccine is preferred to inject into the egg, particularly the amniotic fluid of the egg, of the fowl.
  • the egg is preferred to be fertilized for about 18 days.
  • the preferred fowl includes chicken, turkey, duck, and goose.
  • the DNA construct contains a DNA molecule and a vector.
  • the vector can be a plasmid or a viral carrier.
  • the preferred vector is a plasmid. Examples of the plasmid include, but are not limited to, pcDNA3, pVAX1, pSectag, pTracer, pDisplay, pUC system plasmid (such as pUC7, pUC8, pUC18), and pGEM system plasmid. Alternatively, any plasmid which contains a promoter such as CMV promoter, SV40 promoter, RSV promoter, and ⁇ -actin promoter, can also be used for preparing the DNA construct.
  • the most favorable plasmid is pcDNA3.
  • the preferred viral carrier is one selected from the group consisting of a baculovirus, a herpes virus, and a pox virus.
  • avian virus examples include, but are not limited to Marek's disease virus (MDV), infectious vursal disease virus (IBDV), Newcastle disease virus (NDV), infectious bronchitis virus (IBV), infectious laryngotracheitis virus (ILTV), avian encephalomyelitis (AEV), avian leukosis virus (ALV), fowlpox virus (FPV), avian paramyxovirus (APV), duck hepatitis virus (DHV), and hemorrhagic enteritis virus (HEV).
  • the DNA molecules that are particularly suitable for inducing a protective immune response against the avian viral diseases as shown above include, but are not limited to, the entire of gB gene of Merk's Disease virus (MDV) having the DNA sequence of SEQ ID NO:1 or a fragment thereof; the entire VP2 gene of infectious bursal disease virus (IBDV) having the DNA sequence of SEQ ID NO:2 or a fragment thereof; the entire HN gene of Newcastle disease virus (NDV) having the DNA sequence (which is from bases 6321 to 8319) of SEQ ID NO:3 or a fragment thereof (i.e., SEQ ID NO:3 is the entire genome of the NDV); the entire S1 gene of infectious bronchitis virus (IBV) having the DNA sequence of SEQ ID NO:4 or a fragment thereof; the entire glycoprotein G gene of infectious laryngotracheitis virus (ILTV) having the DNA sequence of SEQ ID NO:5 or a fragment thereof; the entire VP1, VP0, or VP3 gene of
  • DNA vaccine contains two DNA constructs, each containing a DNA molecule capable of expressing a gene or a fragment thereof which is from Marek's disease virus (MDV), infectious vursal disease virus (IBDV), Newcastle disease virus (NDV), or infectious bronchitis virus (IBV).
  • MDV Marek's disease virus
  • IBDV infectious vursal disease virus
  • NDV Newcastle disease virus
  • IBV infectious bronchitis virus
  • Another preferred example of the multiple DNA vaccine contains three or more DNA constructs, each containing a DNA molecule capable of expressing a gene or a fragment thereof which is from Marek's disease virus (MDV), infectious vursal disease virus (IBDV), Newcastle disease virus (NDV), or infectious bronchitis virus (IBV).
  • MDV Marek's disease virus
  • IBDV infectious vursal disease virus
  • NDV Newcastle disease virus
  • IBV infectious bronchitis virus
  • the present invention also provides a method for vaccinating fowl egg and a method for preparing the multiple DNA vaccine.
  • the method for vaccinating fowl egg includes injecting into the fowl egg the multiple DNA vaccine as shown above.
  • the method for preparing the multiple DNA vaccine includes ligating a DNA molecule to a plasmid or virus carrier to form a DNA construct; and then mixing two or more said DNA constructs to form the multiple DNA vaccine.
  • the insertion of the DNA molecule into the vector can be achieved by conventional method, i.e., by ligation the DNA molecule with an enzyme such as T4 DNA ligase when both the genes and the desired vector have been cut with the same restriction enzyme(s) as complementary DNA termini are thereby produced.
  • the preferred restriction enzymes are BamH1 and EcoR1.
  • a multivalent DNA vaccine for in ovo injection.
  • the multivalent DNA vaccine comprises a DNA construct containing two or more DNA molecules linked together with a vector.
  • Each of the DNA molecules expresses an antigenic protein of an avian virus, which is capable of inducing a protective immune response against that avian viral disease in fowl.
  • the multivalent DNA vaccine is preferred to be injected into a fowl egg.
  • Each of the DNA molecules of the multivalent DNA vaccine is a gene or a fragment thereof from Marek's disease virus (MDV), infectious vursal disease virus (IBDV), Newcastle disease virus (NDV), infectious bronchitis virus (IBV), infectious laryngotracheitis virus (ILTV), avian encephalomyelitis (AEV), avian leukosis virus (ALV), fowlpox virus (FPV), avian parainfluenza virus (APV), duck hepatitis virus (DHV), and hemorrhagic enteritis virus (HEV).
  • MDV Marek's disease virus
  • IBDV infectious vursal disease virus
  • NDV Newcastle disease virus
  • IBV infectious bronchitis virus
  • ILTV infectious laryngotracheitis virus
  • AEV avian encephalomyelitis
  • AEV avian leukosis virus
  • FMV fowlpox virus
  • ADV avian parainfluenza virus
  • Traditional avian vaccines comprise chemically inactivated virus vaccines or modified live-virus vaccines. Inactivated vaccines require additional immunizations which are not only expensive to produce but also laborious to administer. Further, some infectious virus particles may survive the inactivation process and may cause disease after administration to the animal.
  • Attenuated live virus vaccines are preferred over inactivated vaccines because they evoke an immune response often based on both humoral and cellular reactions.
  • Such vaccines are normally based on serial passage of virulent strains in tissue culture.
  • the attenuation process induces mutations of the viral genome, resulting in a population of virus particles heterogeneous with regard to virulence and immunizing properties.
  • the traditional attenuated live virus vaccines can revert to virulence resulting in disease outbreaks in inoculated animals and the possible spread of the pathogen to other animals.
  • the resulting DNA vaccines only contain and express the necessary and relevant immunogenic material that is capable of eliciting a protective immune response against the pathogens and would not display above mentioned disadvantages of the live or inactivated vaccines.
  • the DNA sequence of the gene (also used interchangeably as “DNA molecule”) need not contain the full length of DNA encoding the polypeptides. In most cases, a fragment of the gene which encodes an epitope region should be sufficient enough for immunization.
  • the DNA sequence of an epitope region can be found by sequencing the corresponding part of other viral strains and comparing them. The major antigenic determinants are likely to be those showing the greatest heterology. Also, these regions are likely to lie accessibly in the conformational structure of the proteins.
  • One or more such fragments of genes encoding the antigenic determinants can be prepared by chemical synthesis or by recombinant DNA technology. These fragments of genes, if desired, can be linked together or linked to other DNA molecules.
  • RNA viruses need not be in DNA.
  • some of the frequently found avian viral diseases are caused by double- or single-stranded RNA viruses.
  • Marek's diesease virus is a double-stranded RNA virus
  • infectious bursal disease virus (IBDV) Newcastle disease virus (NDV)
  • infectious bronchitis virus (IB) are single-stranded RNA viruses.
  • the RNA viral sequences can be reverse-transcribed into DNA using RT-Polymerase chain reaction (RT-PCR) technology and then incorporated into a vector by the conventional recombinant DNA technology
  • RNA and DNA sequences that encode a specified amino acid sequence.
  • all RNA and DNA sequences which result in the expression of a polypeptide having the antibody binding characteristics are encompassed by this invention.
  • the DNA sequence of the viral gene can be ligated to other DNA molecules with which it is not associated or linked in nature.
  • the DNA sequence of a viral gene can be ligated to another DNA molecule, i.e., a vector, which contains portions of its DNA encoding fusion protein sequences such as ⁇ -galactosidase, resulting in a so-called recombinant nucleic acid molecule or DNA construct, which can be used for transformation of a suitable host.
  • a vector which contains portions of its DNA encoding fusion protein sequences such as ⁇ -galactosidase, resulting in a so-called recombinant nucleic acid molecule or DNA construct, which can be used for transformation of a suitable host.
  • Such vector is preferably derived from, e.g., plasmids, or nucleic acid sequences present in bacteriophages, cosmids or viruses.
  • Plasmids which can be used to clone nucleic acid sequences according to the invention are known in the art and include either a plasmid or a virus carrier.
  • the plasmid include, but are not limited to, pBR322, pcDNA3, pVAX1, pSectag, pTracer, pDisplay, pUC system plasmids (e.g., pUC7, pUC8, pUC18), pGEM system plasmids, Bluescript plasmids or any other plasmids where CMV promoter, SV40 promoter, RSV promoter, or ⁇ -actin promoter is included.
  • the preferred plasmid is pcDNA3.
  • virus carrier examples include, but are not limited to, bacteriophages (e.g., ⁇ and the M13-derived phages), SV40, adenovirus, polyoma, baculoviruses, herpes viruses (HVT) or pox viruses (e.g., fowl pox virus).
  • bacteriophages e.g., ⁇ and the M13-derived phages
  • SV40 e.g., ⁇ and the M13-derived phages
  • adenovirus e.g., ⁇ and the M13-derived phages
  • polyoma e.g., baculoviruses
  • baculoviruses e.g., baculoviruses
  • pox viruses e.g., fowl pox virus
  • nucleic acid sequence into a cloning vector can easily be achieved by ligation with an enzyme such as T4 DNA ligase when both the genes and the desired cloning vehicle have been cut with the same restriction enzyme(s) so that complementary DNA termini are thereby produced.
  • an enzyme such as T4 DNA ligase
  • any restriction site may be produced by ligating linkers onto the DNA termini.
  • linkers may comprise specific oligonucleotide sequences that encode restriction site sequences.
  • the restriction enzyme cleaved vector and nucleic acid sequence may also be modified by homopolymeric tailing.
  • the present invention provides two kinds of DNA vaccines.
  • the first kind is a multiple DNA vaccine, which includes two or more of univalent DNA vaccines, each containing a DNA sequence encoding at least one polypeptide affording protection against one viral disease such as Marek's dosease voris (MDV), infectious bursal disease virus (IBDV), Newcastle disease virus (NDV), infectious bronchitis virus (IBV), infectious laryngotracheitis virus (ILTV), avian encephalomyelitis (AEV), Fowlpox virus (FPV), avian influenza virus (AIV), avian leukosis virus (ALV), duck hepatitis virus B genome, and hemorrhagic enteritis virus (HEV), inserted into a commercially available plasmid.
  • MDV Marek's dosease voris
  • IBDV infectious bursal disease virus
  • NDV Newcastle disease virus
  • infectious bronchitis virus IBV
  • infectious laryngotracheitis virus
  • the second kind is a multivalent recombinant DNA vaccine, which contains two or more genes or gene fragments from different viruses. These genes or gene fragments are carried by a useful vector, which can be either a plasmid or a virus carrier.
  • the multivalent recombinant DNA vaccine encodes two or more antigenic polypeptides which afford protection against at least two viral diseases including, but not limited to, MD, IBD, ND or IB.
  • the viral genes or gene fragments are operatively attached to the vector in reading frame so that they can be expressed in a host.
  • the different structural DNA sequences carried by the vector may be separated by termination and start sequences so that the proteins can be expressed separately or they may be part of a single reading frame and therefore be produced as a fusion protein by methods known in the art.
  • the preferred DNA sequences include, but are not limited to, the entire of gB gene of Merk's Disease virus (MDV) having the DNA sequence of SEQ ID NO:1 or a fragment thereof; the entire VP2 gene of infectious bursal disease virus (IBDV) having the DNA sequence of SEQ ID NO:2 or a fragment thereof; the entire HN gene of Newcastle disease virus (NDV) having the DNA sequence of SEQ ID NO:3 or a fragment thereof; the entire S1 gene of infectious bronchitis virus (IBV) having the DNA sequence of SEQ ID NO:4 or a fragment thereof.
  • MDV Merk's Disease virus
  • IBDV infectious bursal disease virus
  • NDV Newcastle disease virus
  • IBV infectious bronchitis virus
  • the DNA sequence encoding the gB polypeptide of MDV has the nucleic acid sequence as SEQ ID NO:1.
  • the DNA sequence contains 3650 bp of linear DNA.
  • the DNA sequence encoding the VP2 polypeptide of IBDV has the nucleic acid sequence as SEQ ID NO:2.
  • the DNA sequence contains 3004 bp of linear DNA molecule which is reversely transcribed from IBDV's RNA template.
  • the DNA sequence of the entire genome of NDV contains 15186 bps of DNA, wherein (1) base No. 56 to 1792 encodes NP polypeptide, which is nucleocapsid protein; (2) base No. 1804–3244 encodes P polypeptide, which is a phosphoprotein; (3) base No. 3256–4487 encodes M polypeptide, which is a matrix protein; (4) base No. 4498–6279 encodes F polypeptide, which is a fusion protein; (5) base 6321–8319 encodes HN polypeptide, which is a hemagglutinin-neuraminidase; (6) base No. 8370–15073 encodes L polypeptide, which is a large polymerase protein.
  • the NDV genome has the DNA sequence as SEQ ID NO:3.
  • the DNA sequence of the Si polypeptide contains 1611 bp of linear DNA sequence as shown in SEQ ID NO:4, which is reversely transcribed from IBV's RNA templates.
  • IBV infectious bronchitis virus
  • IBD infectious bursal disease
  • ND Newcastle disease
  • DEPC diethylpyrocarbonate
  • Oligonucleotide primers for RT-PCR amplification were purchased from Promega, and were designed according to the genome of the Avian infectious bronchitis virus (Beaudette CK strain), Newcastle disease virus (Lasota strain) and Infectious bursa disease virus respectively.
  • the sequences of the primers used for PCR were:
  • IBS1F′ (SEQ ID NO:12) 5′ CGGGATCCGCCGCCGCCATGTTGGTAACACCTCTT 3′; IBS1R′ (SEQ ID NO:13) 5′ CGGAATTCTTAACGTCTAAAACGACGTGT 3′; NDF F′ (SEQ ID NO:14) 5′ CGGGATCCGCCGCCGCCATGGGCTCCAGACCTTCTACC 3′; NDF R′ (SEQ ID NO:15) 5′ CCGCTCGAGTTACATTTTTGTAGTGGCTCTCATT 3′; NDHN F′ (SEQ ID NO:16) 5′ CGGGATCCGCCGCCGCCATGGACCGCGCCGTTAGGCAAG 3′; NDHN R′ (SEQ ID NO:17) 5′ GCTCTAGATTACTCAACTAGCCAGACCTG 3′; IBDVP2F′ (SEQ ID NO:18) 5′ CGGGATCCGCCGCCGCCATGACAAACCTGCAAGAT 3′; IBDVP2R′ (SEQ
  • Reverse transcription of IBV, NDV and IBDV RNA were carried out at 42° C. for 30 min in 2.5 ⁇ Taq buffer (200 mM NaCl, 15 mM Tris-HCl, pH7.4, 15 mM MgCl 2 , 15 mM ⁇ -mercaptoethanol, and 0.25 mM each of dATP, dCTP, dGTP, and dTTP).
  • the reaction mixture (40 ⁇ l) also contained viral RNA, 2.4 U of avian myeloblastosis virus (AMV) reverse transcriptase (Promega), 16 U of RNasin (Promega), and 0.01 nmol reverse primer (IBDVP2R, NDF F, NDHN F or IBS1R).
  • AMV avian myeloblastosis virus
  • RNasin 16 U of RNasin
  • IBDVP2R 0.01 nmol reverse primer
  • the plasmids pCMV-VP2, pCMV-S1, pCMV-NDF and pCMV-NDHN were constructed with the VP2, S1, NDF and NDHN genes from IBD vaccine, IBV vaccine and NDV vaccine respectively, placed downstream of the commercial plasmid pcDNA3. (Invitrogen, U.S.A.). All of the genes were inserted into the pcDNA3 vector using restriction enzymes BamH1, EcoR1, XbaI and XhoI (underlined characters in the sequence of the primers). Sequences of the all genes in the pcDNA3 vector were verified by sequencing in both directions.
  • the quantity of plasmid DNA that had been purified by affinity chromatography was determined by spectrophotometric measurements at 260 and 280 nm.
  • the DNA in aliquots to 100 ⁇ g was suspended in 100 ⁇ l of PBS (0.14M NaCl, 10 mM sodium phosphate, pH 7.4).
  • PBS 0.14M NaCl, 10 mM sodium phosphate, pH 7.4
  • 1 cc syringe with a 20 gauge 1 and 1 ⁇ 2 inch needle were used.
  • the embryos (18-day-old fertilized and developing eggs from the setting trays) were injected with 0.1 milliliters of DNA vaccine (100 ⁇ g) into the large end of each egg through the air cell with a needle.
  • SPF Specific Pathogen Free fertilized eggs
  • All groups (five eggs each group), all eggs were given 100 ⁇ l in volume each.
  • 100 ⁇ g pCMV-NDF+100 ⁇ g pCMV-NDHN mixture was injected in each egg of group A
  • 100 ⁇ g pCMV-S1 was injected in each egg of group B
  • 100 ⁇ g pCMV-VP2 was injected in each egg of group C
  • 100 ⁇ g pCMV-NDF+100 ⁇ g pCMV-NDHN+100 ⁇ g pCMV-S1(ND+IB) was injected in each egg of group D
  • 100 ⁇ g pCMV-NDF+100 ⁇ g pCMV-NDHN+100 ⁇ g pCMV-VP2 (ND+IBD) was injected in each egg of group E
  • 100 ⁇ g pCMV-VP2+100 ⁇ g pCMV-VP2 mixture IB+IBD
  • All chickens in this experiment were given 100 ⁇ l in volume (1 ⁇ 5 dose of live vaccines), injected into the chicken's thoracic muscle each at 10 days post hatchery.
  • Chickens in group A and I were injected with NDV vaccine
  • group B and J were injected with IBV vaccine
  • group C and K were injected with IBDV vaccine
  • group D were injected with the mixture of NDV+IB vaccines
  • group E were injected with the mixture of NDV+IBD vaccines
  • group F were injected with the mixture of IB+IBD vaccines
  • group G and L were injected with the mixture of NDV, IB and IBD vaccines.
  • the expression of IBDV antigen was not interfered by other monovalent DNA vaccines (NDV and IBV). The same results were also applied to IB and NDV DNA vaccines.

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EP2768529A1 (en) 2011-10-21 2014-08-27 Intervet International B.V. Recombinant nonpathogenic mdv vector providing multivalent immunity
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Publication number Priority date Publication date Assignee Title
US20100075398A1 (en) * 2007-12-13 2010-03-25 Alpharma, Inc. Bacteriophage Preparations and Method of Use Thereof
US8956628B2 (en) 2007-12-13 2015-02-17 Zoetis Products Llc Bacteriophage preparations and method of use thereof
WO2015130492A1 (en) * 2014-02-25 2015-09-03 The United States Of America, As Represented By The Secretary Of Agriculture Novel immunogenic composition
US9950059B2 (en) 2014-02-25 2018-04-24 The United States Of America, As Represented By The Secretary Of Agriculture. Immunogenic composition

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